Fused 1,4-oxazepines as bet protein degraders

Abstract

The present disclosure provides compounds represented by Formula I and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R1, R2a, R2b, R3a, R3b, R4, Ar, L, X, Y, and B areas defined as set forth in the specification. The present disclosure also provids compounds of Formula I for use to treat a condition or disorder responsive to degradation of BET bromodomains such ascancer.

Description

technical field [0001] The present disclosure provides BET bromodomain protein degraders and therapeutic methods for treating conditions and diseases in which degradation of one or more BET bromodomains provides a beneficial effect. Background technique [0002] The genomes of eukaryotes are highly organized within the nucleus of the cell. Long strands of double-helical DNA wind around octamers of histones (usually including two copies of histones H2A, H2B, H3, and H4) to form nucleosomes, which are then further compacted to form highly condensed chromosomal qualitative structure. A range of different states of aggregation is possible, and the compactness of this structure varies during the cell cycle. Chromatin structure plays a key role in regulating gene transcription, and gene transcription cannot efficiently occur from highly condensed chromatin. Chromatin structure is controlled by a series of post-translational modifications to histones, especially histones H3 and ...

AI Technical Summary

Problems solved by technology

BRD2 and BRD3 associate with histones along transcriptionally active genes and may be involved in promoting transcriptional elongation, whereas BRD4 may be involved in recruiting the pTEF-β complex to inducible genes, leading to phosphorylation of RNA polymerase and increased transcriptional output

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